Our overall goal is to develop novel and useful drugs for the control of pain and drug abuse. We have three major aims. The first is a continuation of the original proposal and extends our studies exploring the structure- activity relationships for NaIBzoH (6-desoxy-6-benzoylhydrazido-N-allyl- 14-hydroxydihydronormorphinone), a unique kappa3 agonist/mu antagonist. We have synthesized over 40 analogs of NalBzoH and have observed marked changes in affinity and selectivity with substitutions on the benzoyl ring. Additional compounds are proposed to help understand the importance of the carbonyl and the hydrazone functions. Significant differences also are seen among the naloxone, naltrexone and oxymorphone series which need further study. We will extend these SAR studies to the pharmacological characterization of these agents. In addition to its unique pharmacological profile, NalBzoH has an extremely prolonged dissociation rate from mu receptors which does not correlate with its apparent affinity in equilibrium binding studies. The structural components important in this function also will be explored. The second aim addresses the importance of a previously unrecognized anti-opioid system mediated through sigma1 receptors. Sigma1 agonists block opioid analgesia while sigma antagonists markedly enhance the analgesic activity of all opioid analogs tested. The most profound effects are observed with kappa drugs. We will continue to characterize this system and its interactions with analgesia as well as other opioid functions, including tolerance, dependence, gastrointestinal motility and respiratory depression, and define its effects on the therapeutic index of opioids. The last aim addresses possible mechanisms of action to explain the very high potency of the active morphine metabolite, morphine 6beta-glucuronide (M6G). M6G is over 100-fold more potent than morphine when administered into the brain or spinal canal. Binding studies reveal little difference between morphine and M6G, implying that simple differences in affinity for the receptor are not responsible for the dramatically potency differences. We, will explore the possible role of pharmacokinetics, intrinsic activity and even novel binding sites in the mechanism of action of this agent.